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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rapid development of targeted therapies has tremendously changed clinical management of lung carcinoma patients and set the stage for similar developments in other tumor types. Many studies have been published in the past decade in search for the most acceptable method of assessment for predictors of response to targeted therapies in lung cancer. As a result, several guidelines for molecular testing have been published in a past couple of years. Because of accumulated evidence that targetable drugs show the best efficacy and improved progression survival rates in lung cancer patients whose tumors have a specific genotype, molecular testing for predictors of therapy response has became standard of care. Presently, testing for EGFR mutations and ALK rearrangements in lung adenocarcinoma has been standardized. The landscape of targetable genomic alterations in lung carcinoma is expanding, but none of other potentially targetable biomarkers have been standardized outside of clinical trials. This review will summarize current practice of molecular testing. Future methods in molecular testing of lung carcinoma will be briefly reviewed.
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PMID:Present and future molecular testing of lung carcinoma. 2450 92

The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration.
Lung Cancer 2014 May
PMID:Overcoming the resistance to crizotinib in patients with non-small cell lung cancer harboring EML4/ALK translocation. 2485 2

Lung cancer is the most commonly diagnosed cancer in the world. "Driver" and "passenger" mutations identified in lung cancer indicate that genetics play a major role in the development of the disease, progression, metastasis and response to therapy. Survival rates for lung cancer treatment have remained stagnant at ~15% over the past 40 years in patients with disseminated disease despite advances in surgical techniques, radiotherapy and chemotherapy. Resistance to therapy; either intrinsic or acquired has been a major hindrance to treatment leading to great interest in studies seeking to understand and overcome resistance. Genetic information gained from molecular analyses has been critical in identifying druggable targets and tumor profiles that may be predictors of therapeutic response and mediators of resistance. Mutated or overexpressed epidermal growth factor receptor (EGFR) and translocations in the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) genes (EML4-ALK) are examples of genetic aberrations resulting in targeted therapies for both localized and metastatic disease. Positive clinical responses have been noted in patients harboring these genetic mutations when treated with targeted therapies compared to patients lacking these mutations. Resistance is nonetheless a major factor contributing to the failure of targeted agents and standard cytotoxic agents. In this review, we examine molecular mechanisms that are potential drivers of resistance in non-small cell lung carcinoma, the most frequently diagnosed form of lung cancer. The mechanisms addressed include resistance to molecular targeted therapies as well as conventional chemotherapeutics through the activity of multidrug resistance proteins.
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PMID:Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma. 2463 5

The global landscape of molecular testing is rapidly changing, with the recent publication of the International Association for the Study of Lung Cancer (IASLC)/College of American Pathologists (CAP) guidelines and the ALK Atlas. The IASLC/CAP guidelines recommend that tumors from patients with non-small cell lung cancer (NSCLC) be tested for ALK rearrangements in addition to epidermal growth factor receptor (EGFR) mutations. The spur for this recommendation is the availability of novel therapies that target these rearrangements. This article is based on coverage of a Pfizer-sponsored National Working Group Meeting on ALK Diagnostics in Lung Cancer, held around the 15th World Lung Cancer Conference, in Sydney on October 31, 2013. It is based on the presentations given by the authors at the meeting and the discussion that ensued. The content for this article was discussed and agreed on by the authors.
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PMID:National Working Group Meeting on ALK diagnostics in lung cancer. 2467 36

A 69 year old man with idiopathic chronic kidney disease was diagnosed with relapsing EGFR negative, ALK positive lung adenocarcinoma, and treated with chemotherapy and antiangiogenic treatment, under which his renal insufficiency worsened. During second line crizotinib treatment, further worsening of the renal function was seen, with very clear correlation with crizotinib withdrawal and rechallenge. No further drug causes for the worsening blood creatinine values were detected.
Lung Cancer 2014 Jun
PMID:Crizotinib and renal insufficiency: a case report and review of the literature. 2470 92

ALK inhibitor therapy is individual cancer treatment, in which the targeted drug therapy is directed to a patient group that is likely to benefit from the therapy. The detection in the tumor of ALK gene (anaplastic lymphoma kinase) rearrangement is a prerequisite for the ALK inhibitor therapy for non-small cell lung carcinoma. The ALK assay should be performed for non-squamous cellular non-small cell lung carcinomas, especially adenocarcinomas. It is not recommended to be based on the patients' clinical features. The immunohistochemical method is well suited for screening of ALK positivity. The present recommendation is to ascertain the ALK gene rearrangement from immunopositive specimens by using the FISH procedure.
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PMID:[Diagnostics of non-small cell lung carcinoma]. 2477 87

We herein present a rare case of ALK-positive pulmonary pleomorphic carcinoma in an octogenarian patient. A computed tomography scan of the thorax indicated a pulmonary nodule in the right upper lobe of an asymptomatic 87-year-old female. The surgical resection revealed that the disease was pleomorphic carcinoma with pathological T2aN0M0, stage IB. EML4-ALK was evaluated using immunohistochemistry and fluorescence in situ hybridization, and EGFR mutations were analyzed using the Cycleave method. While there were no EGFR mutations detected, she was positive for the ALK rearrangement. This is the first report of ALK rearrangement in an octogenarian patient with pleomorphic carcinoma of the lung.
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PMID:Detection of ALK rearrangement in an octogenarian patient with pleomorphic carcinoma of the lung. 2484 83

As a result of therapeutic advances, a revolution is taking place in the lung cancer field with major implications for pathologic diagnosis and tissue management. We report a case of a non-small cell lung carcinoma patient with coexistence of EGFR mutations and ALK-EML4 rearrangements that responded to EGFR inhibitors and in which the development of a new resistance mutation in exon 20 of EGFR-determined treatment resistance. All the molecular determinations were performed in cytological samples. To our knowledge, this is the first case reported with these characteristics, and the 11th case described with coexistence of EGFR mutations and ALK-EML4 rearrangements. The EGFR L858R mutation in exon 21 was found at diagnosis, and the patient presented a 4-year response to erlotinib. On progression, the T790M resistance mutation in the EGFR exon 20 was also confirmed in cytological samples. At this point, fluorescence in situ hybridization also detected ALK-EML4 translocation. This case emphasizes the usefulness of cytological samples for molecular analysis in lung adenocarcinoma, as well as the relevance of repeating biopsies/fine-needle aspirations in tumor recurrences to assess the mutation profile of the disease.
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PMID:Variations in molecular profile in NSCLC can be analyzed using cytological samples: development of EGFR resistance mutations and coexistence of ALK-EML4 translocation in an EGFR-sensitive patient. 2494 94

Non-small-cell lung cancer (NSCLC) is the most common cause of cancer-related mortality. Adenocarcinoma (AC) is the predominant histological type of NSCLC; however, AC consists of several subtypes. It has not yet been determined whether there is a correlation of CRKL and AXL expression with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene status in lung AC. We assayed exons 18 through 21 of the EGFR gene by direct sequencing; ALK rearrangement and the expression of CRKL and AXL were detected by immunostaining. A total of 212 cases of AC were included in this study, diagnosed using the novel classification system established by the International Association for the Study of Lung Cancer, the American Thoracic Society and the European Respiratory Society in 2011, including 69 acinar ACs, 17 lepidic predominant ACs (LPAs), 63 papillary, 14 mucinous, 17 micropapillary and 32 solid ACs. Of the 212 cases, 101 harbored EGFR mutations. The most common subtypes carrying delK745-S753 were papillary and acinar ACs. ALK rearrangement was found in 23 cases (11%) of lung ACs. Acinar and solid ACs were the most frequent subtypes with ALK aberrance, particularly in acinar ACs with cribriform structure (4/5 cases, 80%). The expression of CRKL was significantly different among the AC subtypes (P=0.01), with the highest and lowest expression levels of CRKL protein in papillary ACs and LPAs, respectively (P<0.05). AXL expression was also significantly different among the AC subtypes (P=0.002) and was correlated with lymph node infiltration in acinar ACs. ACs with EGFR mutations exhibited high levels of AXL protein expression compared to those without mutations (P<0.001). Acinar AC with cribriform structure is a distinct subtype that frequently harbors ALK rearrangement. The activation of AXL may be one of the factors contributing to the invasion of acinar and micropapillary ACs.
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PMID:Differential expression of CRKL and AXL genes in lung adenocarcinoma subtypes according to the epidermal growth factor receptor and anaplastic lymphoma kinase gene status. 2494 92

Tumor tissue biomarkers are the basis for targeted therapy in non-small cell lung cancer (NSCLC). These biomarkers either reflect the target of the specific drug or some factor that might abrogate the effect of the drug. These targeted drugs are small-molecule inhibitors of a specific tyrosine kinase or a monoclonal antibody against a specific receptor. In this review, tissue biomarkers in NSCLC and companion diagnostics will be described, followed by an overview of targeted therapy to EGF/EGFR, HER2, VEGF/VEGFR, ALK, KRAS, BRAF, MEK and MET and some of the newer potential targets. Recent initiatives include the Lung Cancer Matrix Network, the BATTLE trials and the Lung Cancer Mutation Consortium. There are a number of key clinical trials in targeted therapy in NSCLC which will be reporting during the next year.
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PMID:Current status of targeted therapy in non-small cell lung cancer. 2510 32


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